The first critical step in melanocytic tumor progression is the transition between a benign nevus, which is a self-limited localized proliferation of melanocytes, and the radial growth phase (RGP) of malignant melanoma, which may be in situ or micro-invasive but is non-tumorigenic, and is not capable of metastasis. The second critical step is from RGP to vertical growth phase melanoma (VGP), which is invasive and tumorigenic and may have capacity for metastasis. The next critical step is the development of metastasis. Our overall goal is to develop new diagnostic and prognostic markers for these critical steps of progression. Our working hypothesis is that new diagnostic and progression markers for these critical steps of progression. Our working hypothesis is that integrin adhesion receptors play critical roles in progression, and that shifts in expression of these adhesion receptors during progression coincide with shifts in expression of growth factors, proteolytic enzymes, factors regulating cell cycle and apoptosis, and transcription factors, as well as altered adhesion to matrix molecule Our preliminary studies have identified the beta3 subunit of the vitronectin receptor has a critical determinant of the progression from RGP to VGP. However, to date the field lacks reliable markers for RGP and nor is the marker of markers for VGP sufficient. In the planned investigations we will systematically investigate expression of relevant invasion and growth-related molecules in nevi including dysplastic nevi and in RGP and VGP primary melanoma using a stepwise strategy from global expression analysis by representational difference analysis and by DNA microarrays, to in situ protein and mRNA detection in single cell levels. Selected markers will then be include in models for the diagnosis of RGP and VGP and for the prognosis of VGP melanoma, These analyses will rest in the development of markers that will greatly improve our ability to greatly improve our ability to diagnose malignant melanoma versus dysplastic nevi and other melanoma stimulants, as well as our ability to predict survival rates in patients with primary melanoma. Thus, they will also have considerable impact on therapy.